NIH Mentored Clinical Scientist Research Career Development Award (K08) Application FOA number: PA-14-046 Project: Evolution of resistance of EGFR mutant non-small cell lung cancer Applicant: Aaron Hata Project Summary/Abstract Advances in our understanding of the genetic alterations in cancer have given rise to effective therapies that target specific oncogenic signaling pathways. For instance, treatment of non-small cell lung cancers (NSCLCs) harboring activating mutations in the epidermal growth factor receptor (EGFR) with small molecule EGFR inhibitors leads to dramatic clinical responses. Unfortunately, the clinical effectiveness of targeted therapies is limited by the inevitable emergence of acquired drug resistance that ultimately renders the therapy ineffective. Understanding these mechanisms of resistance is fundamental to developing improved treatment strategies to improve patient outcomes. In this project, Dr. Hata proposes to study the evolution of acquired resistance of EGFR mutant NSCLC. Dr. Hata is an Instructor in Medicine at Harvard Medical School and a member of the Hematology/Oncology faculty at the Massachusetts General Hospital Cancer Center. As a Hematology/Oncology Fellow in the Dana Farber/Partners CancerCare Oncology Training program, Dr. Hata joined the laboratory of Dr. Jeffrey Engelman in the MGH Center for Cancer Research in 2010, where he has focused on understanding how changes in apoptotic signaling affect sensitivity and resistance to targeted therapies. Since joining the MGH faculty in 2013, Dr. Hata has continued his research studies in the Engelman Laboratory, and is now interested in applying insights gained from his prior work toward understanding how EGFR mutant NSCLC resistant clones emerge and evolve during therapy. Dr. Hata recently demonstrated that genetic mechanisms of resistance such as the EGFRT790M mutation can evolve de novo from surviving drug tolerant cells during drug treatment, suggesting that drug tolerant cells that do not yet harbor genetic mechanisms of resistance can serve as an important reservoir for subsequent evolution of resistance. In this project, Dr. Hata proposes to investigate the evolution of acquired resistance of EGFR mutant NSCLC to EGFR inhibitors in patients. Examining tumor biopsy specimens from patients at the time of disease progression for genetic signatures that accumulate in drug tolerant cells, he will determine whether resistant cancers derived from pre-existing resistant sub-clones or evolved during therapy. He will integrate analysis of tumor cells from patients undergoing EGFR inhibitor therapy with functional studies using laboratory tumor models derived from these same patients to characterize drug tolerant tumor cells in vivo. Finally, he will investigate novel drug treatment strategies designed to target drug tolerant cells in vivo. These studies will significantly enhance our understanding of how acquired drug resistance evolves in the clinic and identify novel treatment strategies that delay or prevent emergence of resistance. To accomplish these studies, Dr. Hata will leverage the research and clinical resources of the Engelman Lab, the MGH Cancer Center and the larger Dana Farber/Harvard Cancer Center community. Under the primary mentorship of Dr. Engelman, he will collaborate closely with experts in the field of genomics and epigenetics, as well as clinicians within the MGH Thoracic Oncology and Interventional Pulmonology groups. To oversee his scientific and career development, he has established a mentoring committee of both internal and external faculty who have extensive expertise in basic and translational oncology and proven track records of mentoring junior faculty during the transition to independence. He has created a career development plan designed to facilitate development of specific skills in genomics and bioinformatics that will enable him to be a successful independent investigator. This project will lead to novel insights into the evolution of acquired resistance to EGFR inhibitors in NSCLC as well as resistance to targeted therapies in general, and will inform future treatment strategies designed to delay or prevent acquired resistance in the clinic. Additionally, this project will provide critical research and training support for Dr. Hata as he establishes himself as an independent investigator in the field of translational lung cancer research. !